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Endoplasmic reticulum (ER) stress causes cell survival or death, which is dependent on the type of cell and stimulus. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) and its analog, dihydrocapsaicin (DHC), induced caspase-3-independent/-dependent signaling pathways in WI38 lung epithelial fibroblast cells. Here, we describe the molecular mechanisms induced by both chemicals. Exposure to capsaicin or DHC caused induction of p53, p21, and G 0 /G 1 arrest. DHC induced massive cellular vacuolization by dilation of the ER and mitochondria. Classic ER stress inducers elicited the unfolded protein response (UPR) and up-regulation of microtubule-associated protein 1 light chain-3 (LC3) II. DHC induced ER stress by the action of heavy chain-binding protein, IRE1, Chop, eukaryotic initiation factor 2␣, and caspase-4 and, to a lesser level, by capsaicin treatment. DHC treatment induced autophagy that was blocked by 3-methyladenine (3MA) and accumulated by bafilomycin A1. Blocking of DHC-induced autophagy by 3MA enhanced apoptotic cell death that was completely inhibited by Capsaicin (8-methyl-N-vanillyl-6-nonenamide), a representative pungent ingredient found in the red pepper of the genus Capsicum, has been known to induce selectively apoptosis in malignant cells but not in normal cells, which is ascribed to the generation of reactive oxygen species by blocking of the plasma membrane electron transport system (Morré et al., 1995;Macho et al., 1999). In a previous study, capsaicin-induced apoptosis in ras-transformed human breast epithelial cells (H-ras MCF10A), but not in the parental MCF10A cells,

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